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Neuropharmacology > Pharmacokinetics & Pharmacodynamics > Flashcards

Pharmacokinetics & Pharmacodynamics Flashcards

1
Q

pharmacokinetics

A

how conc. of drug changes in body with time

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2
Q

ADME

A

absorption
distribution
metabolism
elimination

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3
Q

clinical aim of drug administration

A

achieve effective drug conc. (in therapeutic range) at site of action (systemic circulation) long enough to have an effect

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4
Q

therapeutic window vs index

A

window refers to population while index refers to individual patient
wider box - wider range so safe

used to use LD50 (conc that kills 50% population) divided by ED50 (effective dose)
but not ethical

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5
Q

bioavailability

A

proportion of dose of unchanged drug that reaches site of action

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6
Q

intravenous injection

A

100% bioavailability because straight to systemic circulation
need sterile equip, trained, expensive, painful

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7
Q

oral route (plus and minuses)

A

safest, most convenient, economical, always less than 100% bioavailability because destroyed by bacteria/acid/food/enzymes
absorption depends on rates of passage
some side effects and requires patient co-operation

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8
Q

drug absorption from GI tract to circulation

A

Fick’s law of passive diffusion

rate = (permeability x SA x conc diff) / thickness of membrane

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9
Q

what does permeability of drug depend on?

A

its lipid solubility

lipid soluble and small will pass better

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10
Q

most drugs are….

and what is better absorbed?

A

weak acids/bases and unionised drugs are better absorbed

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11
Q

other absorption methods

A

active transport
ion-pair absorption (+ve ion with -ve ion in gut forms neutral complex moves into blood)
pinocytosis engulfs
solvent drug (highly lipid soluble drug won’t dissolve in lumen so dissolve in solvent before drink)

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12
Q

sites of drug absorption

A

little absorption: small intestine (main site), stomach, colon

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13
Q

formulation

A

strong enough so don’t fall apart when handle but still dissolve

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14
Q

gut motility

A

gastric emptying modulated by meal size/composition, drugs, physiological state (lay/sit), migraine

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15
Q

orally administered drugs with potential problems

A

phenoxymethyl penicillin - absorbed by food so take on empty stomach
tetracyclines - absorption reduced by milk/antacids/iron
aspirin - iritate stomach

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16
Q

1st pass metabolism

A

before systemic

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17
Q

if drug rapidly metabolised by liver/gut then other routes?

A

inhalation - avoids 1st pass metabolism, straight to systemic

transdermal - across skin, hard to get across e.g. nicotine patches, ibuprofen gel

buccal+sublingual - gum+under tongue, straight to systemic

intranasal

rectal

subcutaneous - upper dermis not in muscle

intramuscular injection - large blood flow in muscles so reliable route, but can’t self administer

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18
Q

penicillin administration

A 
route affect bioavailability
oral - slow
IV - fast
IM - fast and longer duration
P-IM - modified IM with much longer duration
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19
Q

plasma protein binding (function, free drug, what binds what, saturation of binding

A

drugs in plasma bound to proteins which act as buffer/carrier
only free drug is active and eliminated but free can cause toxic effects

weak acids bind plasma albumin
weak bases bind acid glycoprotein

saturation of binding is non linear relationship between dose and free conc.
a small increase in drug conc. causes large increase in free drug so toxic

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20
Q

tissue distribution of drug depends on….

A

depends on lipid solubility, plasma protein binding and molecular weight
e.g. heparin is big so doesn’t leave plasma

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21
Q

blood brain barrier

A

hard to get drugs into brain, and it pumps drugs out to have low conc.

because layer of tightly joined endothelial cells, contain P-glycoprotein (Pgp) efflux pump

lipid soluble drugs by passive diffusion
water soluble by carrier mechanisms

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22
Q

drug metabolism in liver by hepatocytes (what happens, and explain process)

A

some converted to inactive metabolites
some to active metabolites
some excreted unchanged

Phase 1 (primary metabolites): transform molecular structure of drug

Phase 2 (secondary metabolites): conjugation - attachment of endogenous substance to original drug or after phase 1, by transferases

to increase water solubility, make polar, abolish activity

then excretion

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23
Q

excretion

A

renal route via kidney

can change urinary pH to aid excretion
some drugs actively excreted like penicillin

dangerous if drug excreted unchanged

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24
Q

other routes of excretion

A

biliary into intestine - bile to gal bladder to small intestine so can absorb back into blood - enterohepatic circulation

saliva, sweat, tears, expired
breast milk - danger to baby

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25
Q

Vd

A

apparent (not real) volume of distribution

not real because some conc. of drug in plasma so small that tells you large volume than humans have

so just tells you if distributed in tissues or plasma

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26
Q

fraction extracted

A

E= (conc in - conc out)/ conc in

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27
Q

clearance

A

how well gets rid of drug

rate of elimination/conc of input

volume/time (virtual volume of blood cleared of drug per unit time)

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28
Q

creatine clearance rate

A

linear relationship between drug clearance and creatine clearance so high conc in blood means poor clearance

better than taking periodic blood samples to see drug conc change

29
Q

measuring clearance

A

creatine clearance
blood sample
renal clearance - urine samples

30
Q

normal clearance for healthy

A

88-128 mL/min women

97-137 mL/min male

31
Q

clearance and age

A

decreases with age so half life of drug goes up and need to adjust dosage intervals

32
Q

first order elimination kinetics (most drugs)

A

rate of elimination proportional to drug conc. - exponential so faster elimination more drug

33
Q

kel

A

elimination rate constant
units time-1
proportion of drug eliminated per unit time

kel= rate of elimination/amount left

34
Q

time constant

A

1/kel

time taken for conc. to fall 1/e (37%)

35
Q

half life

A

time taken for drug conc to fall by half

ln2/kel

helps determine dosage interval

36
Q

2 exponentials of elimination

A

distribution to other compartments
then slower rate elimination
both 1st order kinetics

37
Q

Ka

A

absorption rate constant

38
Q

phases of drug in body

A

lag time (time to get to blood)
absorption (plasma conc builds up)
elimination (eliminate/distribute)

39
Q

area under curve of plasma conc (y) against time after ingestion (x)

A

AUC

bioavailability of drug so amount absorbed

40
Q

loading dose

A

injection to start then orally maintain level of conc.

better than oral when need immediate effect

41
Q

continuous infusion

A

slowly build conc. of drug over time (rapid is bad for BP) with infusion/pump
to eliminate troughs in oral graph so get smooth curve and eliminate toxicity if use loading dose

42
Q

zero order kinetics

A

rate of elimination not proportional to drug conc but is constant
e.g. ethanol
if you start with more drug it takes longer to remove it so half life is not constant but depends on starting conc.

so constant amount eliminated

43
Q

drug dosage changes

A

neonates have reduced body volume and higher proportion of water so reduce dose
reduce dose in elderly because higher fat than water, drug binding to plasma proteins reduced

low renal function and clearance at birth and reduced in elderly

lower metabolism

44
Q

drug monitoring

A

monitor conc level in blood if toxic/effective

take sample at peak conc./trough conc./time above threshold value

45
Q

urine sample to monitor drug

A

useful so don’t need blood and for drugs partially/fully eliminated in urine
but volume variable because how much drink so can’t use drug conc. but absolute amount (moles)

46
Q

drug modes of action

A 
enzyme inhibitors
enzyme false substrates
receptor activators
receptor blockers
ion channel blockers
ion channel modulators
neurotransmitter uptake blockers
47
Q

measuring response

A

force of contraction, current, change in potential, amount of 2nd messenger (cAMP), loss of NT, physiological change

48
Q

EC50

A

conc that gives 50% of max response

49
Q

why is there a max response?

A

finite no. receptors so all occupied

or property of tissue/cell so can’t contract any more because max reached

50
Q

affinity

A

how well drug binds receptor (not about the response)

51
Q

efficacy

A

measure of response - how well turns receptor on to active form
low means can’t reach max response

52
Q

potency

A

combine affinity and efficacy

53
Q

k+1

k-1

A

association rate constant

dissociation rate constant

54
Q

Kd

A

conc. of drug required to occupy 50% receptors

(k-1)/(k+1)

lower Kd means less drug needed so high affinity

55
Q

measuring affinity

A

can’t measure contraction because measures efficacy as well

ligand binding assay - radio label ligand and shows when bind to receptor so radioactive shows how much bound

but must account for non-specific binding

56
Q

non-specific binding

A

low affinity so keeps binding and doesn’t reach max - straight line
saturate with cold ligand (without label) so any radioactivity is binding to non-specific sites so subtract off total binding to get specific binding

57
Q

desensitisation/tachyphylaxis

A

bound for long time to phosphorylated and receptor internalised so less response because less receptors or run out of mediators

tachyphylaxis is whole organ or tissue no longer responds

58
Q

clinical agonists

A

adrenaline - increase HR and force contraction for anaphylactic shock (allergy)
salbutamol for asthma
dopamine increase HR
morphine for severe pain

59
Q

partial agonsts

A

partial response
same affinity but not full response
conc. doesn’t matter

e.g. to reduce over-activity but not block basal activity, e.g. pain killer or treat addicts

60
Q

basal activity (constitutive)

A

receptor’s activity in absence of ligand

61
Q

partial beta agonists

A

beta-blockers slow heart but don’t block all beta receptors

62
Q

inverse agonists

A

reduce basal activity of G-protein receptors (reduces response below 0)
many antagonists are inverse agonists

63
Q

GABA-A receptor

A

main inhibitory receptor in brain
control excitation
2 binding sites for Gaba, 1 for barbiturates
B2 full agonist binds to separate site to increase opening when GABA binds (inverse agonists would bind here and decrease opening)

64
Q

barbiturates

A

A barbiturate is a drug that acts as a central nervous system depressant and can therefore produce a wide range of effects, from mild sedation to death.

65
Q

competitive antagonists

A

binds to receptor but doesn’t do anything but prevent agonist binding so no response
enough agonist can outcompete antagonist
don’t change max response but shift curve to right because more conc needed for 50% response

66
Q

measurement of potency pA2

A

-ve log of molar conc. of antagonist that reduces effect of known conc of agonist to that of 1/2 conc.
(how good at blocking agonist response)
bigger value better antagonist

67
Q

non-competitive antagonists

A

bind allosteric site or covalently to main site and stay there
diff slope gradient and not max response curve

none clinically used, but some toxins

68
Q

spare receptors

A

sometimes don’t need to occupy all receptors to get full response (e.g. only 70% needed)
use non-competitive antagonists to get full response
if still get full response then have spare receptors

so conc. for 50% receptors is not conc. for 50% response (Kd not EC50)

Neuropharmacology (3 decks)

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